The arginine-vasopressin (AVP) is a peptide composed of nine amino acids, is biosynthesized mainly in the hypothalamus, and is highly involved in regulation of plasma osmolality, blood pressure, and body fluid volume as a posterior pituitary hormone.
Three subtypes of AVP receptors, V1a, V1b, and V2 receptors, have been cloned until now. They are all known to be seven-transmembrane receptors. The V2 receptor is coupled to Gs to increase the cAMP level. The V1a receptor is coupled to Gq/11 to facilitate PI response and increase the intracellular Ca level. The V1a receptor is expressed in, for example, the brain, liver, adrenal gland, and vascular smooth muscle and is involved in vasoconstriction. The V1b receptor is also coupled to Gq/11, like the Via receptor, to facilitate PI response (see Non-Patent Literatures 1 and 2). The V1b receptor is observed most commonly in the pituitary gland (expressed in 90% or more ACTH secreting cells of the anterior lobe) and is supposed to participate in the ACTH secretion from the anterior pituitary by AVP. The V1b receptor is present in various areas of the brain at high levels: the limbic cortex system including the hippocampus, amygdala, and entorhinal cortex, the cerebral cortex, the olfactory bulb, and the raphe nucleus, which are the origin of the serotonin nervous system, in addition to the pituitary gland (see Non-Patent Literatures 3 and 4).
In recent years, involvement of the V1b receptor in mood disorder or anxiety disorder has been suggested, and usefulness of V1b receptor antagonists has been being studied. The V1b receptor KO mice exhibit reduced aggressive behavior (see Non-Patent Literature 5). In addition, injection of a V1b receptor antagonist in the septal area prolonged the time spent in the open arm (anxiolytic-like effect) in an elevated plus-maze test (see Non-Patent Literature 6). In recent years, a V1b receptor specific antagonist, a 1,3-dihydro-2H-indol-2-one compound that can be administered peripherally, has been discovered (see Patent Literatures 1 to 3). In addition, the 1,3-dihydro-2H-indol-2-one compound was reported to show antidepressant- and anxiolytic-like effects in a variety of animal models (see Non-Patent Literatures 7 and 8). The compound disclosed in Patent Literature 1 shows a high affinity (1×10−9 mol/L to 4×10−9 mol/L) for and selectively acts on the V1b receptor, and this compound antagonizes AVP, AVP+CRF, and restraint stress-induced ACTH increases.
Recently, V1b receptor antagonists having structures different from that of the 1,3-dihydro-2H-indol-2-one compound have been reported, such as quinazolin-4-on derivatives (see Patent Literatures 4 and 10), β-lactam derivatives (see Patent Literatures 5 and 7), azinon/diazinon derivatives (see Patent Literature 6), benzimidazolone derivatives (Patent Literature 8), isoquinoline derivatives (see Patent Literatures 9 and 10), pyridopyrimidin-4-one derivatives (see Patent Literature 11), pyrrolo[1,2-a]pyrazine derivatives (see Patent Literature 12), pyrazolo[1,2-a]pyrazine derivatives (see Patent Literature 13), tetrahydroquinoline sulfonamide derivatives (see Non-Patent Literature 9), and thiazole derivatives (see Non-Patent Literature 10). However, compounds with a 1,2,4-triazolone skeleton disclosed in the present invention have not been reported.